Genetic and non‐genetic risk factors for pre‐eclampsia: umbrella review of systematic reviews and meta‐analyses of observational studies

Abstract

Short title: Genetic and non-genetic risk factors for preeclampsia Keywords: Preeclampsia, Risk factors, Epidemiology, Meta-analysis, Umbrella reviewThis article is protected by copyright. All rights reserved.This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/uog.18959 Accepted Article AbstractObjective: To summarize evidence from the literature on the risk factors associated with preeclampsia, assess the presence of statistical biases and identify associations with robust evidence. Methods:We searched PubMed and ISI Web of Science from inception to October, 2016, to identify systematic reviews and meta-analyses of observational studies examining associations between genetic and non-genetic risk factors for preeclampsia.For each meta-analysis we estimated the summary effect size by random-effects and fixed-effects models, the 95% confidence interval and the 95% prediction interval. We estimated the between-study heterogeneity expressed by I 2 (considering above 75% as very large), evidence of small-study effects (large studies had significantly more conservative results than smaller studies and evidence of excess significance bias (too many studies with statistically significant results).Results: Fifty-seven eligible papers were identified providing data on 130 associations including 1466 primary studies, covering a very wide range of risk factors: co-morbid diseases, genetic factors, exposure to environmental agents and a range of biomarkers.Sixty-five (50%) associations had nominally statistically significant findings at P<0.05, while sixteen (12%) were significant at P<10 -6 . Sixty-four (49%) associations had large or very large heterogeneity. Evidence for small-study effects and excess significance bias was found in ten (8%) and twenty-six (20%) associations, respectively. Oocyte donation vs normal conception (OR 4.33, 95% CI: 3.11-6.03) had >1000 cases, 95% prediction intervals excluding the null, not suggestive of large heterogeneity (I 2 <50%), small-study effects (P for Egger's test>0.10), or excess of significance (P>0.05

The clinical heterogeneity of preeclampsia is related to both placental gene expression and placental histopathology

“…4,10 Causes of PE are multifactorial in nature with genetic, environmental, and maternal constitutional contributions that have yet to be fully elucidated. 11 While it is believed that placental dysfunction underlies the majority of PE cases, 12 heterogeneity in clinical presentation and outcomes, disease severity, and placental pathology between women with PE suggest that multiple forms of placental disease in PE exist. 13 For example, aspirin is most effective in reducing the recurrence of preterm, but not term, PE and reduces the risk of PE in women with risk factors for the disease.…”

Bisphenol A exposure alters placentation and causes preeclampsia‐like features in pregnant mice involved in reprogramming of DNA methylation ofWNT2

“…Among risk factors for preeclampsia, environmental and genetic ones are considered equally important (5). Maternal exposure to the environmental chemical BPA may be an important risk factor for abnormal placentation (6)(7)(8) and subsequent pregnancy complications such as preeclampsia (9,10).…”

Placenta-Specific Genes, Their Regulation During Villous Trophoblast Differentiation and Dysregulation in Preterm Preeclampsia

“…This allowed the determination of RNA levels but not protein levels. Another limitation is that RNA microarrays are unable to reveal the expression of polymorphic gene variants, which may have a role on preterm preeclampsia [115,116]. In future studies, next-generation sequencing may help reveal these variants.…”